Alzheimer's disease is a disease characterized by nerve cell degeneration and loss as well as formation of senile plaques and neurofibrillary change. Currently, treatment of Alzheimer's disease is limited to symptomatic treatment using symptom improving agents represented by acetylcholine esterase inhibitors, and no basic remedy for suppressing progression of the disease has been developed. Development of a method for controlling the cause of the pathological conditions is necessary to create a basic remedy for Alzheimer's disease.
It is thought that the Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter, referred to as APP), is closely involved in degeneration and loss of nerve cells and further development of dementia symptoms (for example, refer to Non-patent document 1 and Non-patent document 2). The major components of the Aβ protein are Aβ40, which consists of 40 amino acids, and Aβ42, which has two more amino acids at the C terminus. These Aβ40 and Aβ42 have a high agglutination property (for example, refer to Non-patent document 3) and are the major components of a senile plaque (for example, refer to Non-patent document 3, Non-patent document 4, and Non-patent document 5). Further, mutation of the APP and presenilin genes observed in familial Alzheimer's disease is known to increase these Aβ40 and Aβ42 (for example, refer to Non-patent document 6, Non-patent document 7, and Non-patent document 8). Therefore, compounds that decrease production of Aβ40 and Aβ42 are expected as drugs for suppressing progression of or preventing Alzheimer's disease.
Aβ is generated by cleavage of APP by beta secretase followed by excision by gamma secretase. Based on this, development of inhibitors of gamma secretase or beta secretase has been attempted for the purpose of suppressing production of Aβ. Many of these known secretase inhibitors are peptides or peptide mimetics such as, for example, L-685458 (for example, refer to Non-patent document 9) and LY-411575 (for example, refer to Non-patent document 10, Non-patent document 11, and Non-patent document 12).    [Non-patent document 1] Klein W L, and 7 others, Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceedings of the National Academy of Science USA 2003, Sep. 2; 100(18), p. 10417-10422    [Non-patent document 2] Nitsch R M, and 16 others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554    [Non-patent document 3] Jarrett J T, and 2 others, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, 32(18), p. 4693-4697    [Non-patent document 4] Glenner G G, and another, Alzheimer's disease: initial report of the purification and Characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical Research Communications, 1984, May 16, 120(3), p. 885-890    [Non-patent document 5] Masters C L, and 5 others, Amyloid plaque core protein in Alzheimer's disease and Down's syndrome, Proceedings of the National Academy of Science USA, 1985, June, 82(12), p. 4245-4249    [Non-patent document 6] Gouras G K, and 11 others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, January, 156(1), p. 15-20    [Non-patent document 7] Scheuner D, and 20 others, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, August, 2(8), p. 864-870    [Non-patent document 8] Forman M S, and 4 others, Differential effects of the Swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and normeuronal cells, The Journal of Biological Chemistry, 1997, Dec. 19; 272(51), p. 32247-32253    [Non-patent document 9] Shearman M S, and 9 others, L-685458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity, Biochemistry, 2000, Aug. 1; 39(30), p. 8698-8704    [Non-patent document 10] Shearman M S, and 6 others, Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and β-APP Cleavages, Biochemistry, 2003, Jun. 24; 42(24), p. 7580-7586    [Non-patent document 11] Lanz T A, and 3 others, Studies of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575), The journal of Pharmacology and Experimental Therapeutics, 2004, April; 309(1), p. 49-55    [Non-patent document 12] Wong G T, and 12 others, Chronic treatment with the γ-secretase inhibitor LY-411575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, The Journal of Biological Chemistry, 2004, Mar. 26; 279(13), p. 12876-12882